Alendronate sodium is chemically known as (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt. Alendronate as disclosed in U.S. Pat. No. 4,621,077, is a specific inhibitor of osteoclast-mediated bone resorption and is indicated for the treatment of urolithiasis and inhibiting bone reabsorption.
Alendronate is commercially available as alendronate sodium trihydrate in the form of tablets and oral solution under the trade name Fosamax® (Merck). Tablets have certain disadvantage for patients who are unable to swallow tablets readily. To overcome the problem of difficulty in swallowing, alendronate in solution formulation have been developed with an increased patient compliance. Commercially available alendronate oral solution contain 91.35 mg of alendronate monosodium salt trihydrate, which is molar equivalent to 70 mg of free acid alendronate as active ingredient and excipients such as sodium citrate dihydrate and citric acid anhydrous as buffering agents, sodium propylparaben 0.0225% and sodium butylparaben 0.0075% as preservatives, sodium saccharin, artificial raspberry flavor and purified water.
Given below are the patents/patent publications, which disclose aqueous oral formulations of alendronate.
U.S. Pat. No. 4,814,326 discloses aqueous solution of diphosphonic acid with amino carboxylic acid as stabilizer with pH 4.5-5.65.
U.S. Pat. No. 5,462,932 discloses composition comprising a pharmaceutically effective amount of alendronate, in a pharmaceutically acceptable carrier and a sufficient amount of a buffer to maintain a pH of the composition in the range of 2 to 8 and complexing agent to prevent the precipitation of alendronate sodium in aqueous solution.
U.S. Pat. No. 5,994,329 discloses liquid composition comprising alendronate monosodium trihydrate, sodium propylparaben, sodium butylparaben, sodium citrate dihydrate, citric acid anhydrous, sodium saccharin, sodium hydroxide and water.
US 2003/0139378 discloses an oral liquid composition comprising: a) a therapeutically effective amount of at least one bisphosphonate or a pharmaceutically acceptable salt thereof, b) a pharmaceutically acceptable carrier, and c) a pharmaceutically acceptable buffer, wherein a dose of said oral liquid pharmaceutical composition has a buffering capacity sufficient to buffer at least 50 mL of 0.1 N HCl to a pH of greater than or equal to 3.5.
US 2004/087550 discloses a composition for prevention of metabolic diseases of bones comprising: at least one bisphosphonate including alendronate sodium, viscosity agents comprising carboxymethylcellulose and xanthan gum; at least one flavoring agent and purified water.
WO 98/14196 discloses an aqueous liquid formulation comprising: alendronic acid; a sufficient amount of a buffer such that the pH of the formulation is between approximately 3.5 and approximately 7.5 and 15 ml of the formulation is able to raise the pH of 50 ml 0.1N HCl to a pH of at least 3 and optionally, one or more additional agents selected from the group consisting of preservatives, flavoring agents, colorants, and sweeteners.
WO 08/028547 discloses liquid composition for prevention of bone metabolic diseases, comprising alendronic acid or its acceptable pharmaceutical salts, or mixtures thereof, a viscosity agent selected from the group consisting of alginate, propylglycolalginate, arabic gum (acacia), xanthan gum, guar gum, locust bean, carrageenan gum, karaya gum, tragacanth gum, chitosan, sodium carboxymethyl cellulose and carbomer or mixtures thereof, at least one flavoring agent and purified water.
The above prior art references discloses various liquid formulations of alendronate sodium using amino carboxylic acid, buffer, viscosity agents and complexing agent to stabilize alendronate in aqueous formulations.
However, still there is a need to develop stable aqueous formulation comprising alendronate wherein said formulation is free of buffers and stabilizers. The inventors of the present invention surprisingly found that stable alendronate solution can be prepared by maintaining pH less than 5.0 using inorganic acid without using any buffers and stabilizers.